This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Like most other sexually transmitted diseases (STDs), HIV's primary site of infection is at mucosal surfaces, and like most other STDs, there is no vaccine for HIV. The proposed study will explore the possible use of the oral mucosal route for immunization against HIV/STDs through induction of immunity at distal sites mediated via the common mucosal immune system. We will characterize innate, adaptive cellular, and humoral responses in the periphery and in mucosal (oral, nasal, pulmonary and rectal) sites to vaccines given at 2 oral mucosal sites (submucosal immunization in the buccal fossa and over the lingual tonsil). Rhesus macaques, will be immunized with a SIV version of one of the leading HIV vaccine regimens: DNA prime/replication-incompetent Ad5 vaccine boost. We will test whether submucosal immunization over the lingual tonsil produces robust peripheral B- and T-cell responses. Adaptive responses will be measured in the blood and at mucosal sites;antigen-specific T cells will be measured using ELISpot and intracellular cytokine staining and antibody will be measured by ELISA. Possible mechanisms underlying differences in adaptive responses elicited by different routes will be investigated via studies of innate immune responses (systemic dendritic cell phenotype and function, and serum cytokine/chemokine profiles). This study will provide data on whether vaccination of the oral mucosa can provide protection against sexually transmitted organisms, through induction of immunity at distal sites (such as the rectum) mediated by the common mucosal immune system. It will also investigate the usefulness of this route of immunization for protection against respiratory pathogens, such as influenza, when immunity in the nose and lungs is desired.